- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03660683
Effect of Saxagliptin and Dapagliflozin on Endothelial Progenitor Cell in Patients With Type 2 Diabetes Mellitus
Cardio-Protective of Effect of Saxagliptin and Dapagliflozin Combination on Endothelial Progenitor Cells in Patients With Type 2 Diabetes
The Investigator hypothesize that Dapagliflozin will improve EPC number and function AND Saxagliptin in addition to Dapagliflozin (additive effect) may improve EPC number and function even more than Dapa alone, compared to placebo.
The Investigator propose a 3-arm randomized, parallel group, longitudinal study of 16-week intervention duration. Participants will be randomized to 3 groups:
Group A: Dapa (10 mg) + Saxa Placebo, Enroll n=15, retain n=12 Group B: Dapa (10 mg) + Saxa (5 mg), Enroll n=15, retain n=12 Group C: Dapa Placebo + Saxa Placebo, Enroll n=15, retain n=12
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
The Investigator hypothesize that Dapagliflozin will improve EPC number and function AND Saxagliptin in addition to Dapagliflozin may have an additive effect to improve EPC number and function even more than Dapa alone, compared to placebo.
In this proposal the investigator plan to conduct a placebo matched study with type 2 diabetes subjects on any doses of metformin or Insulin or a combination of both and has no history of DPP4 ( Dipeptidyl Peptidase-4) DPP4 inhibitor, incretin mimetic or SGLT2 inhibitor intake history. Participants will have known macrovascular complications (such as Cardiovascular Disease (CVD), Cerebrovascular Accident (CVA), and Peripheral Vascular Disease (PVD).
3 STUDY OBJECTIVES
PRIMARY OBJECTIVE:
CELLULAR BIOMARKER OF ENDOTHELIUM
The primary objective is to ascertain if 16 weeks of Dapa or Dapa+Saxa Combo therapy will improve :
CD34+ cell number, CD34+ migratory function and CD34+ gene expression in type 2 diabetes with CVD.
SECONDARY OBJECTIVE:
ARTERIAL STIFFNESS AND RENAL FUNCTION, NON-CELLULAR MARKERS OF ENDOTHELIUM To determine whether use of Dapa or Dapa+Saxa Combo alters markers of endothelial function such as: arterial stiffness measures (via tonometry), biochemical measures derived from plasma, pertaining to endothelial function (hs-CRP, IL-6, TNF-alpha), renal function such as proteinuria (microalbumin/creatinine ratio) and urine exosome study to determine podocyte health. The secondary measures are indirect measures of endothelial inflammation in early type 2 diabetes patients.
Effect on Arterial Stiffness:
I. Pulse Wave Analysis and Vascular Flow will be assessed using SphygmoCor CP system from ATCOR as a measure of central arterial pressure and arterial stiffness.
II. Vessel health will be assessed by degree of arterial stiffness, using arterial tonometry.
III. The central and the aortic pressure is assessed by pulse wave analysis (PWA) and pulse wave velocity (PWV).
Effect on Blood Biochemistry:
The Investigator believes cell based biomarkers are superior to traditional serum and plasma biomarkers and the outcome report will be stronger if one can show positive correlation between the two outcome measures. The Investigator therefore will be looking at:
I. Inflammation, apoptosis and anti-oxidant protein levels: Highly selective C-reactive protein (hs-CRP), IL-6, TNF-alpha.
II. Plasma SDF1 alpha (ELISA) and GLP-1 and Ghrelin (ELISA) will be estimated to assess endothelial health and factors that may influence CD34+ cell chemotaxis III. Podocyte health via urine exosome analysis. IV. The glomerular filtration rate (GFR) will be estimated by MDRD equation.
a. GFR = 141 X min (Scr/κ,1)α X max(Scr/κ,1)-1.209 X 0.993Age X 1.018 [if female] X 1.159 [if African American]; where Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1.32
TERTIARY OBJECTIVE:
METABOLISM MARKERS The tertiary objective is to determine whether use of Dapa or Dapa+Saxa Combo alters body composition, fasting lipid profile, and levels of insulin, glucose, and appetite controlling hormones.
Effect on Blood Biochemistry:
The Investigator believes cell based biomarkers are superior to traditional serum and plasma biomarkers and the outcome report will be stronger if one can show positive co-relation between the two outcome measures.
I. Fasting glucose, and insulin. a. Glycemic control will be evaluated by measuring fasting blood glucose, insulin levels and HbA1c. Fasting blood glucose, insulin and lipid profile will be used to assess insulin resistance.28,31 II. Lipid profile III. Appetite controlling hormones via LabCorp: Leptin, Adiponectin IV. Appetite controlling hormones, via ELISA: GLP1, Ghrelin
Effect of Dapa and Dapa+Saxa Combo on Body Habitus (Determination of body composition and visceral fat) The Investigator plans to study cardio-metabolic effect of Dapa and Dapa+Saxa Combo.
I. Using body composition scale:
- Height and weight will be measured and the body mass index (BMI=kgm2) used as an indicator of relative weight.
The body composition scale calculates body fat%, total body water%, fat free mass, etc., in addition to BMI.
The secondary outcome markers (arterial stiffness and renal outcome measures) and tertiary outcome markers (serum biochemistry) are crucial in order to corroborate the cellular findings with currently accepted clinical efficacy outcome measures such as arterial stiffness and serum biochemistry. This design is similar to our recently published manuscript on Saxagliptin and cellular outcome measures.
4 INVESTIGATIONAL PLAN
STUDY DESIGN AND DURATION
+/- 6 day window for visits
*Assessed at week 0, 8 and 16: Primary, Secondary & Tertiary Outcomes.
Week 20: A telephone call to subjects will be made 4 weeks after last dose of study medication to determine if there have been any adverse events.
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
District of Columbia
-
Washington, District of Columbia, United States, 20037
- The GW Medical Faculty Associates
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Able to understand the study, and provide a signed & dated informed consent.
- Diagnosis of Type 2 diabetes mellitus using criteria of the American Diabetes Association.
- 30-70 years old.
- HbA1C 7 to 10%, both inclusive
- BMI of 25 - 39.9 kg/m2 both inclusive.
- Taking a stable dose (for 12 weeks) of Metformin (any dosage) and/or Insulin (any dosage) for the treatment of T2DM
Patients with current Cardiovascular Disease (CVD) in tye 2 diabetes patients, defined by ≥ 1 of the following:
- MI >2 months prior
- Multivessel CAD
- Angina (intermittent or chronic)
- Single vessel CAD with positive stress test or UA hospitalization in prior year
- UA >2 months prior and evidence of CAD
- Stroke >2 months prior
- Occlusive PAD
- Proteinuria of more than 30mg/dl
Exclusion Criteria:
- Planned CV surgery or angioplasty in 1 month
- Prior surgery with chronic malabsorption (eg, bariatric) in prior 1 year
- Diagnosis of Type 1 diabetes mellitus
- History of GAD antibody positive status
- Uncontrolled Inflammatory Disease/Inflammatory drug use. **Evaluated by PI on case-by-case basis**
- Recent history of diabetic keto-acidosis in the past 3months, or recurrent history of diabetic ketoacidosis (≥ 3 times)
- Active bladder cancer
- Active wounds (e.g. Diabetic ulcers) or recent surgery within 1 month
- Untreated hyper/hypothyroidism
- Women of child bearing potential who are not willing to use a contraceptive method to avoid pregnancy for the 16 weeks of study duration
- Women who are pregnant or breastfeeding
- Implanted devices (eg. Pacemaker) that may interact with Tanita scale
- Any other clinical condition that would jeopardize patients safety while participating in this clinical trial Concomitant Medications
- Taking any other oral anti-diabetic agent other than Metformin and/or Insulin for their treatment of T2DM
- Beginning statin medications in the past 1 month or change in statin dose in the past 1 month
- Use of consistent long-term steroid medication (oral, inhaled, injected) within the last 1 month
- Treatment with a strong cytochrome P450 3A4 (CYP34A) or P-gp inducer (ie. Rifampin)
- Subjects with a history of any serious hypersensitivity reaction to Dapagliflozin / Saxagliptin or another SGLT-2 inhibitor/ DPP4 inhibitor Laboratory Findings
- Uncontrolled hyperglycemia, defined as a fasting glucose >240 mg/dL (>13.3 mmol/L) at screening.
- Liver disease with ALT, AST or ALP x3 ULN
- eGFR < 60 mL/min/1.73 m2 by MDRD equation in the past 3 months
- Clinically significant RBC disorders such as hemoglobinopathies
- Serum creatinine levels ≥1.8 mg/dL with estimated eGFP < 60 mL/min
- Triglycerides > 450 mg/dL
- Baseline Hematuria (judged by a urinalysis dipstick at screening) Social History
- Active smokers
- Chronic or persistent alcohol or drug abuse
- Prisoners or subjects who are involuntarily incarcerated
- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg. infectious disease) illness
- Participation in another trial with an investigational drug within 30 days prior to informed consent
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Group A Dapa
Dapagliflozin 10 mg + Saxagliptin Placebo
|
Dapagliflozin 10mg PO QD
Other Names:
|
Active Comparator: Group B DapaSaxa
Dapagliflozin 10mg + Saxagliptin 5mg
|
Dapagliflozin 10mg PO QD
Other Names:
Saxagliptin 5 mg PO QD
Other Names:
|
Placebo Comparator: Placebo
Placebo Oral Tablet
|
Matching Placebo Tablets
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
CD 34+ Cell Migratory Function
Time Frame: 16 weeks
|
Proportion of cells that migrate through SDF1a in a transwell assay.
This proportion is represented as a migratory rating scale from 0-1, with 1 being 100% of cells migrate.
A larger value indicates better migratory function of the CD34+ cells.
|
16 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
CD 34+ Cell Gene Expression
Time Frame: 16 weeks from visit 1
|
Fold change of Gene Expression in T2Dm with CVD relative to visit 1
|
16 weeks from visit 1
|
CD 34+ Cell Fraction
Time Frame: 16 weeks
|
Quantifying CD34+ cells is based on proportion of the monocytes that are CD34+ to account for any variations in cell harvesting or death during analysis.
|
16 weeks
|
Arterial Stiffness - Augmentation Index
Time Frame: 16 Weeks
|
Augmentation index was calculated via tonometry with Sphygmocor Device (Pulse Wave Analysis).
Augmentation index is calculated as the augmentation pressure (the amplitude of the reflected pulse wave) divided by the pulse pressure (systolic - diastolic) * 100 to give a percentage of pulse pressure.
The software then calculates an estimated Augmentation Index at heart rate of 75 as a form of "normalization."
Lower values are generally preferred as they indicate more pliable and healthy arteries.
|
16 Weeks
|
Blood Biochemistries
Time Frame: 16 Weeks
|
hsCRP
|
16 Weeks
|
Renal Function
Time Frame: 16 Weeks
|
Microalbumin/Creatinine Ratio (Proteinuria)
|
16 Weeks
|
Urine Exosome Assay
Time Frame: 16 Weeks
|
Protein western analysis of Exosomes released from Kidney Podocyte is a indicator of kidney Podocyte health. Expressed as a ratio normalized to CD9 expression |
16 Weeks
|
Arterial Stiffness
Time Frame: Week 16
|
Pulse Wave Velocity
|
Week 16
|
Arterial Stiffness - Augmentation Pressure
Time Frame: 16 Weeks
|
Augmentation index was calculated via tonometry with Sphygmocor Device (Pulse Wave Analysis). Augmentation index is calculated as the augmentation pressure (the amplitude of the reflected pulse wave) divided by the pulse pressure (systolic - diastolic) * 100 to give a percentage of pulse pressure. The software then calculates an estimated Augmentation Index at heart rate of 75 as a form of "normalization." Lower values are generally preferred as they indicate more pliable and healthy arteries. Here, augmentation pressure is shown as a reference for the Augmentation Index calculations in the previous section. |
16 Weeks
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Fasting Lipid Profile
Time Frame: 16 Weeks
|
Total Cholesterol, LDL, HDL and VLDL
|
16 Weeks
|
Serum Insulin Level
Time Frame: 16 Weeks
|
Measured in fasting state at visit
|
16 Weeks
|
Serum Glucose
Time Frame: 16 Weeks
|
Fasting Glucose level measured in serum
|
16 Weeks
|
Appetite Controlling Hormone
Time Frame: 16 Weeks
|
Leptin, (Adiponectin, GLP1, Ghrelin in separate entry)
|
16 Weeks
|
Serum Glucose
Time Frame: 16 Weeks
|
HbA1C (estimate of serum glucose over 3 months)
|
16 Weeks
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Sabyasachi Sen, MD, PhD, GWU
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Glucose Metabolism Disorders
- Metabolic Diseases
- Endocrine System Diseases
- Cardiovascular Diseases
- Diabetes Mellitus
- Diabetes Mellitus, Type 2
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Protease Inhibitors
- Incretins
- Sodium-Glucose Transporter 2 Inhibitors
- Dipeptidyl-Peptidase IV Inhibitors
- Dapagliflozin
- Saxagliptin
Other Study ID Numbers
- 180295
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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